A genome-wide association study of psychosis and its characteristic endophenotypes

Lead Research Organisation: University College London
Department Name: Division of Psychiatry

Abstract

GENETICS OF PSYCHOSIS AT PRESENT
Psychotic disorders affect 2% of the population and are within the seven leading causes of disability (WHO). Although psychotic disorders run in families and neuregulin 1 and dysbindin are promising candidate genes, unambiguous risk genes remain elusive. Genome-wide association allows testing hundreds of thousands of markers across the entire human genome in large samples and has successfully led to the identification of nearly 200 genes in 70 common illnesses like diabetes and heart disease. However, psychiatric diagnoses do not constitute easy traits for genetic research and I propose using biomarkers as an alternative. These biomarkers are quantitative biological traits characterising psychosis which are obtained by laboratory-based methods.

AIMS OF THIS PROJECT
To use a genome-wide scan to examine the association between genetic variation and
(iii) psychosis (in a conventional case-control design)
(iv) biological markers of brain function or structure that are characteristic of the disease.

WHAT WE PROPOSE TO DO
From twin and family studies I selected the most suitable psychosis biomarkers. These include deficits in memory and other cognitive abilities as well as changes in brain activity and structure measured by EEG tests and MRI scans. I organised an international consortium to obtain DNA samples and biomarker data from 7,000 individuals [1,500 patients, 2,500 relatives and 3,000 controls]. The USA ?Consortium On the Genetics of Schizophrenia?, a comparable independent study, provides an opportunity for replications. A genome-wide scan of this sample is almost complete and this will provide more than one million genetic markers in what is the largest and most comprehensive genetic study of a psychiatric disease to date.

I am currently in my final year of my post-doctoral fellowship (Department of Health) and I now seek support from the MRC to continue to lead the analysis of this highly valuable sample and to establish myself as an independent researcher in the process.

HOW THIS RESEARCH COULD HELP
Elucidation of susceptibility genes for psychosis and the mechanisms by which these genes convey risk for the disease will advance the understanding and treatment of psychosis.

Technical Summary

Background:
Although psychotic disorders are highly heritable and neuregulin 1 and dysbindin are promising candidate genes, unambiguous risk variant(s) remain elusive. Genome-wide association has successfully led to the identification of nearly 200 loci in 70 common illnesses with complex genetics. However, psychiatric diagnoses do not constitute optimal phenotypes for genetic research and I propose using biomarkers (endophenotypes) as an alternative. Endophenotypes are quantitative biological traits characterising psychosis which are obtained by laboratory-based methods.

Aims:
To use a genome-wide scan to examine the association between genetic variation and
(i) psychosis (in a conventional case-control design)
(ii) biological markers of brain function or structure (endophenotypes) that are characteristic of the disease.

Methods:
From twin and family studies the most suitable psychosis endophenotypes were selected: (i) cognitive deficits affecting verbal memory, digit span and block design performance, (ii) neurophysiologic deficits in the P300 wave from the human electroencephalogram, and (iii) neuro-anatomical abnormalities in whole brain and lateral ventricular volumes.

During my Department of Health post-doctoral fellowship I organised an international consortium to obtain DNA and clinical diagnoses from 7,000 individuals [1,500 patients, 2,500 relatives and 3,000 controls]. Of these a large proportion had cognitive, neuro-anatomic and neurophyisologic endophenotypes ascertained. The USA Consortium On the Genetics of Schizophrenia, a comparable independent study, provides an opportunity for replications.

I obtained a 2-year grant to fund the genotyping of this sample as part of the Wellcome Trust Case Control Consortium. A genome-wide scan using Affymetrix 6 is almost complete and will provide 1M SNPs as well as extensive copy number variation data. Analysis of quantitative endophenotypes can be performed in PLINK. Sib-pair, singleton and twin data will be investigated for association using the variance components methodology.

I now seek support from the MRC to continue to lead this psychosis consortium in the analysis of our highly valuable dataset and to establish myself as an independent investigator in the process.

Publications

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Bigdeli TB (2016) Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Broome MR (2010) Neural correlates of movement generation in the 'at-risk mental state'. in Acta psychiatrica Scandinavica

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Carletti F (2012) Alterations in white matter evident before the onset of psychosis. in Schizophrenia bulletin

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Crossley NA (2012) Neurophysiological alterations in the prepsychotic phases. in Current pharmaceutical design

 
Description Biomedical Research Centre at UCL (Mental Health Theme)
Amount £5,000,000 (GBP)
Organisation University of Leicester 
Department NIHR Biomedical Research Centre
Sector Hospitals
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description British Medical Association's Margaret Temple Fellowship
Amount £50,000 (GBP)
Organisation British Medical Association (BMA) 
Sector Learned Society
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description European Commision Marie Curie post-doctoral fellowship
Amount € 190,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2013 
End 05/2015
 
Description European Commision Marie Curie post-doctoral fellowship
Amount € 185,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2017 
End 07/2019
 
Description John Grace QC PhD studentship
Amount £85,000 (GBP)
Organisation Mental Health Research UK (MHRUK) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description MRC - KHIDI collaborative grant
Amount £18,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 06/2017
 
Description MRC Cenary Award - Title: A Study of Neural Connectivity in Psychosis and Populations at Genetic Risk.
Amount £94,530 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 01/2013
 
Description MRC project grant - Title: Low coverage sequencing for the detection and analysis of genomic structural variants in schizophrenia
Amount £1,000,000 (GBP)
Funding ID G1100583 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2014
 
Description Project Grant - Wellcome Trust Case Control Consortium 2 - Genome wide association study of psychosis endophenotypes
Amount £1,400,000 (GBP)
Funding ID 084779 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Title Database contributed to Psychiatric Genomics Consortium 
Description The data from my genome-wide association study, duly annonymised has been contributed to the Psychiatric Genomics Consortium (PGC). The PGC constitutes the largest international collaboration in psychiatry and has identified 60 new SNPs influencing risk for schizophrenia. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2012 
Provided To Others? Yes  
Impact This research material is now part of the largest mega-analysis of genetic data in psychiatric diseases. This international collaboration (where I have contributed) has identified 60 SNPs that influence the risk of developing schizophrenia. This is an important landmark in the field of psychiatric genetics. 
 
Title Public access database - GWAS of psychosis 
Description Anonymous individual data from my GWAS is now available for any researcher to access. Open access for research purposes. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Data used by many international collaborations. Has resulted in several high profile papers, for example in Nature 
 
Description Psychiatric Genomics Consortium 
Organisation Cardiff University
Department Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution I have contributed phenotypic data and samples from my GWAS study.
Collaborator Contribution The Psychiatric Genomics Consortium is contributing data for the replication of my GWAS study to assist with the replication of my findings
Impact Multidisciplinary
Start Year 2011
 
Description Psychiatric Genomics Consortium 
Organisation University of North Carolina at Chapel Hill
Department Department of Psychiatry
Country United States 
Sector Academic/University 
PI Contribution I have contributed phenotypic data and samples from my GWAS study.
Collaborator Contribution The Psychiatric Genomics Consortium is contributing data for the replication of my GWAS study to assist with the replication of my findings
Impact Multidisciplinary
Start Year 2011
 
Description The Psychosis Endophenotypes International Consortium 
Organisation Heidelberg University Hospital
Department Department of Psychiatry
Country Germany 
Sector Hospitals 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Psychosis Endophenotypes International Consortium 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Department of Psychiatry and Psychotherapy
Country Germany 
Sector Hospitals 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Psychosis Endophenotypes International Consortium 
Organisation Maastricht University (UM)
Department Division of Cognitive Neuropsychiatry and Clinical Neuroscience
Country Netherlands 
Sector Academic/University 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Psychosis Endophenotypes International Consortium 
Organisation University of Cantabria
Department Marqués de Valdecilla University Hospital
Country Spain 
Sector Hospitals 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Psychosis Endophenotypes International Consortium 
Organisation University of Edinburgh
Department Division of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Psychosis Endophenotypes International Consortium 
Organisation University of Western Australia
Department School of Psychiatry and Clinical Neurosciences
Country Australia 
Sector Academic/University 
PI Contribution I am the PI of the study and I lead this consortium.
Collaborator Contribution Contributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaborationContributed DNA samples and phenotypes for collaboration
Impact This is still an early phase of the collaboration and we have no joint publications yet.
Start Year 2008
 
Description The Wellcome Trust Case Control Consortium 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution This collaboration had the aim to undertake a genome wide association study (GWAS) of psychosis endophenotypes. My team and I contributed a large sample of patients with psychotic disorders, their unaffected relatives and healthy controls. I recruited several clinical teams across Europe, Australia and the US and we all contributed the samples, phenotypes and DNA. I was then directly involved in the data quality control, statistical analysis and writing of manuscripts.
Collaborator Contribution The Wellcome Trust funded the study. The Sanger Institute coordinated the molecular work The WT Centre for Human Genetics in Oxford coordinated the analysis of the data.
Impact This is a multidisciplinary collaboration including medicine-psychiatry, genetics, bioinformatics and statistics. OUTPUTS 1) Several high profile papers. Please see my publication list. 2) We developed a large database that is for public access to all researchers wishing to use it world wide.
Start Year 2008
 
Description The Wellcome Trust Case Control Consortium 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration had the aim to undertake a genome wide association study (GWAS) of psychosis endophenotypes. My team and I contributed a large sample of patients with psychotic disorders, their unaffected relatives and healthy controls. I recruited several clinical teams across Europe, Australia and the US and we all contributed the samples, phenotypes and DNA. I was then directly involved in the data quality control, statistical analysis and writing of manuscripts.
Collaborator Contribution The Wellcome Trust funded the study. The Sanger Institute coordinated the molecular work The WT Centre for Human Genetics in Oxford coordinated the analysis of the data.
Impact This is a multidisciplinary collaboration including medicine-psychiatry, genetics, bioinformatics and statistics. OUTPUTS 1) Several high profile papers. Please see my publication list. 2) We developed a large database that is for public access to all researchers wishing to use it world wide.
Start Year 2008
 
Description The Wellcome Trust Case Control Consortium 
Organisation Wellcome Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution This collaboration had the aim to undertake a genome wide association study (GWAS) of psychosis endophenotypes. My team and I contributed a large sample of patients with psychotic disorders, their unaffected relatives and healthy controls. I recruited several clinical teams across Europe, Australia and the US and we all contributed the samples, phenotypes and DNA. I was then directly involved in the data quality control, statistical analysis and writing of manuscripts.
Collaborator Contribution The Wellcome Trust funded the study. The Sanger Institute coordinated the molecular work The WT Centre for Human Genetics in Oxford coordinated the analysis of the data.
Impact This is a multidisciplinary collaboration including medicine-psychiatry, genetics, bioinformatics and statistics. OUTPUTS 1) Several high profile papers. Please see my publication list. 2) We developed a large database that is for public access to all researchers wishing to use it world wide.
Start Year 2008
 
Description Animated film on psychosis - public engagement in science 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Film in public domain. Presented at film festivals. Raises public understanding of psychosis. Reduces stigma of mental illness.

I have been invited to several panels of discussion.
Year(s) Of Engagement Activity 2014
 
Description Interview in live TV 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview lead to better public understanding of recent genetic advances in psychosis

Have been asked for further similar requests.
Year(s) Of Engagement Activity 2014
 
Description NAAT 2010 reported_Academic Presentation as a key note speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact World congress psychiatric genetics
Year(s) Of Engagement Activity 2010
 
Description NAAT 2012 reported_Academic Poster Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited plenary talk at international congress
Year(s) Of Engagement Activity 2012
 
Description Psychiatry international conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited plenary speaker
Year(s) Of Engagement Activity 2016
 
Description State of the art speaker at the World Psychiatric Association International Congress - Taipei 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two oral presentations at this large international congress with more than 500 delegates. Q&A session followed. Two excellent collaborations emerged from this conference.
Year(s) Of Engagement Activity 2015